The compound 3,4-methylenedioxymethamphetamine, MDMA (street name "ecstacy") is a phenylisopropylamine derivative which displays structural similarities to both the amphetamines and hallucinogens, but has a distinct psychopharmacological profile from either class. In humans, MDMA produces a state of heightened awareness, decreases anxiety and promotes or facilitates communication. Recently, the recreational use of MDMA has escalated. Furthermore, biochemical and pharmacological studies indicate that repeated MDMA administration is neurotoxic towards serotonergic neurons in rats and primates. However, relatively few studies have assessed the long term effects of repeated MDMA administration on serotonergic neuronal function. Therefore, the specific aim of this research proposal is to examine the effect of multiple MDMA injections on pre- and postsynaptic serotonergic neuronal function. We shall record from spontaneously active cells in the medial prefrontal cortex (mPFc) and test their response to 5-HT and selective 5-HT agonists using standard single unit recording and microiontophoretic techniques in chloral hydrate anesthetized male Sprague Dawley rats. Experiments will be carried out in control (saline treated) and (+)-MDMA treated rats. In addition, the effect of electrical stimulation of the caudal linear nucleus of the raphe on mPFc cell firing in (+)-MDMA and control rats will be examined and compared. Furthermore, the effect of intravenously administered (+)-MDMA on the firing rate of mPFc cells in rats exposed to multiple doses of MDMA will be examined. The extent of the neurotoxicity or nerve terminal destruction produced by MDMA will be determined by receptor autoradiography using 3H-paroxetine binding, which labels 5-HT uptake sites. Finally, we will assess various indices of serotonergic function 0.5, 1, 3, 6 and 12 months after the last exposure to MDMA to ascertain if there is a recovery of function. These results will be correlated with those obtained with receptor autoradiography of 5-HT uptake sites. Our approach should yield important data regarding the effects of repeated MDMA administration on pre- and postsynaptic serotonergic function over a protracted period of time.